This invention relates to an inhibitor for neovasculation, cell multiplication, lumen formation and fibroblast growth factor (FGF), wherein the active component is a tocotrienol, and a food and a food additive containing tocotrienol.
Neovasculation is the formation of a new blood vessel from an existing blood vessel, and is composed of the following steps. (1) Neovasculation factor transfers a neovasculation signal to an endothelial cell, and the endothelial cell digests basement lamina and extracellular substrate in the neighborhood. (2) The hemoendothelial cell wanders while it multiplies. (3) The hemoendothelial cell forms lumen (neovasculation), and forms capillaries reticularly. It is observed that the neovasculation occurs on the onset and progress of diseases, such as a solid tumor, diabetic retinopathy, rheumatoid arthritis, hemangioma, periodontal disease, scleroderma, glaucoma, psoriasis and age-related macular degeneration, and it is considered to advance the progress of each disease. Various neovasculation inhibitors have been developed, but none of them have been put to practical use. Accordingly, it is still desired to develop a compound having safe neovasculation-inhibitory activity without side effects.
By the way, an inhibitor for the synthesis of heat-shock proteins having a molecular weight of 47 kilo daltons is known comprising tocopherol or a derivative thereof as an active component (JA09 040556A). The derivative includes the homologs of tocotrienol, i.e. xcex1-, xcex2-, xcex3- and xcex4-tocotrienols. The invention intends the treatment of diseases which produce extracellular matrices, such as cirrhosis of the liver and scleroderma, and discloses that the fibrosis accompanied with these diseases is caused by the increase of collagen synthesis, and that collagen synthesis increases with increasing the development of the above heat-shock proteins. Furthermore, it is pointed out that collagen synthesis in basement lamina exhibits an important role in neovasculation, and the inhibitor for the synthesis of heat-shock proteins is effective for the diseases based on the abnormal growth of neovasculation, i.e. diabetic retinopathy, glaucoma, rheumatic arthritis, etc. However, it is also taught that xcex1-tocopherol, which is vitamin E, is the most preferred, and only xcex1-tocopherol is shown in the Examples. Tocotrienols are only listed in the derivatives of tocopherol.
On the other hand, it is said that tocophenols have no action to inhibit neovasculation, the inventors also confirmed this matter in the following comparative examples.
An object of the invention is to provide an inhibitor exhibiting inhibitory action against neovasculation, cell multiplication, lumen formation and fibroblast growth factor (FGF), which has no problem in safety and is far superior to xcex1-tocopherol, and to contribute to the treatment of diseases caused by abnormal growth of neovasculation.
The inventors investigated eagerly in order to achieve the above object, and as a result, they found that tocotrienols, especially xcex2-, xcex3-, xcex4-tocotrienols, have a much greater inhibitory action against neovasculation, cell multiplication (cell growth), lumen formation and FGF than xcex1-tocopherol to complete the invention.
Thus, the present invention provides;
A neovasculation inhibitor which comprises xcex2-, xcex3-, xcex4-tocotrienol as an active component,
A cell multiplication inhibitor which comprises xcex2-, xcex3-, xcex4-tocotrienol as an active component,
A lumen formation inhibitor which comprises xcex2-, xcex3-, xcex4-tocotrienol as an active component,
A fibroblast growth factor inhibitor which comprises xcex2-, xcex3-, xcex4-tocotrienol as an active component.=,
A food containing a tocotrienol selected from the group consisting of xcex1-tocotrienol, xcex2-tocotrienol, xcex3-tocotrienol and xcex4-tocotrienol, and
A food additive comprising a tocotrienol selected from the group consisting of xcex1-tocotrienol, xcex2-tocotrienol, xcex3-tocotrienol and xcex4-tocotrienol.